The role of natural killer cells in the control of tumor growth and metastasis.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Biomedical subjects
N Hanna
Publications and source records attributed to N Hanna.
Binding of histamine and histamine analogs to lymphocyte subsets analyzed by flow cytometry.
The binding of histamine, 4-methylhistamine (a histamine type 2 receptor agonist), cimetidine (a histamine type 2 receptor antagonist), and telemethylhistamine (an inactive analog) to human peripheral blood mononuclear cell subsets was investigated by flow cytometry by using conjugates of these ligands coupled to fluorescein-labeled human serum albumin. Our results indicate that binding of fluorescent protein conjugates of histamine and its analogs does not selectively identify a lymphocyte subset(s) that mediates the immunomodulatory effects of histaminergic ligands. Conjugates with both low (2.5 to 2.8:1) and high (28 to 57:1) ligand to protein coupling ratios were used. No binding above background could be detected for the low mole ratio reagents. The high mole ratio reagents were bound by 95 to 99% of all lymphocytes when used at ligand concentrations of 50 microM or greater. At lower ligand concentrations, the number of lymphocytes exceeding a set fluorescence threshold was decreased, but fluorescence distributions remained unimodal at all concentrations used (1 to 500 microM). Monocytes also bound the high mole ratio reagents and gave rise to a second high-intensity peak in the fluorescence distribution unless they were excluded by other means. Levels of conjugate binding detected by flow cytometry did not parallel ligand potencies at classical histamine type 2 receptors; at equivalent ligand concentrations, approximately equal amounts of histamine or 4-methylhistamine conjugate were bound per lymphocyte, and only 30% less telemethylhistamine conjugate was bound. Competition with free ligands (10(2)- to 10(4)-fold excess histamine, 4-methylhistamine, cimetidine, or telemethylhistamine) did not significantly decrease the level of binding observed for the high mole ratio reagents at bound ligand concentrations of 1 to 25 microM. Dual staining with fluorescein-labeled conjugate and phycoerythrin-labeled monoclonal antibodies Leu-3ab (anti-helper T), Leu-2a (anti-suppressor T), Leu-M3 (anti-monocyte), or anti-HLA-DR (B cells and monocytes) was also carried out. The extent of conjugate binding to helper and suppressor cells was identical for each of the ligands used, but higher levels of conjugate binding were seen for monocytes and B cells than for T cells in every case. Our data do not exclude the possibility of enhanced conjugate binding to small numbers of activated (HLA-DR positive) T cells that might be involved in mediation of histamine effects.(ABSTRACT TRUNCATED AT 400 WORDS)
Binding Sites↗
Modulation of macrophage-lymphocyte interactions by the antiarthritic gold compound, auranofin.
Auranofin (AF), a new oral gold agent effective for treating rheumatoid arthritis (RA) was evaluated for its ability to alter macrophage and lymphocyte functions of immune mediated chronic inflammation. AF (2 microM) inhibited antigen presentation by splenic macrophages to sensitized (DNFB) lymph node cells in vitro and also inhibited production of IL-2 and IL-1 by lymphocytes and macrophages, respectively. When AF suppressed Con-A induced mitogenesis in vitro, there were no inhibitory effects on Con-A induced suppressor T cell functions. AF administered orally to normal mice did not affect antigen presentation. DNFB contact sensitivity or Con-A induced mitogenesis. High concentrations of topical AF inhibited local immune responses to contact sensitizing agents and enhanced the induction of antigen specific suppressor T cells. Optimally, in vitro or in vivo AF inhibited macrophage and helper T cell functions with impairing the induction of suppressor T cells. After chronic treatment, similar effects could contribute to the efficacy of AF in humans with RA.
Animals↗
Suppressed IL-2 production and response in AA rats: role of suppressor cells and the effect of auranofin treatment.
The marked suppression of mitogenic responses to concanavalin A observed in adjuvant arthritic (AA) rats during the development and progression of the clinical disease is mediated primarily by splenic adherent cell population. The suppressed mitogenic response of spleen cells from AA rats was in part due to suppressed production of and response to interleukin 2 (IL-2). Unfractionated spleen cells from AA rats did not produce or respond to IL-2. However, IL-2 production and response were normalized after removal of adherent cells. Reconstitution experiments demonstrated that adherent cells from AA rats suppressed both the mitogenic response and IL-2 production by normal spleen cells. The low IL-2 levels was not a result of degradation or consumption of endogenously produced interleukin. In vitro treatment of suppressor adherent cells from AA rats with micromolar concentrations of auranofin (AF), but not gold sodium thiomalate, totally abolished the suppression of both mitogenesis and IL-2 production. Our studies demonstrate that the suppressed lymphocyte mitogenic responses, IL-2 response and IL-2 production of AA rat spleen cells are due to the presence of suppressor adherent cells, and that treatment with AF inhibited suppressor cell activity and restored to normal levels lymphocyte mitogenic responses and IL-2 production.
Animals↗
Inhibition of T suppressor cell expression by histamine type 2 (H2) receptor antagonists.
The effect of histamine type 2 (H2) receptor antagonists, cimetidine and ranitidine, on the induction and expression of hapten-specific suppressor T cells was studied. The activity of DNBSO3 -induced suppressor cells was evaluated after adoptive transfer to naive syngeneic recipients. Treatment with cimetidine or ranitidine markedly inhibited suppressor T cell activity in a dose-related manner and enhanced the contact sensitivity response to DNFB. Both H2 antagonists were effective in inhibiting the expression and, to a lesser extent, the induction of suppressor T cells. In contrast, norburimamide , a non-H2 antagonist structurally related to cimetidine, was inactive. The relevance of these findings to the clinical observation of cimetidine-induced reversal of acquired tolerance to dinitrochlorobenzene in anergic patients is discussed.
Animals↗
A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice.
The ability of the human A375 melanoma cell line to produce experimental and spontaneous in young BALB/c nude mice was examined. Cloned lines, obtained by isolation in semisolid agar, differed significantly (4/10 cloned lines examined, P less than or equal to .005) from the parent tumor line with regard to their ability to form lung tumor nodules subsequent to iv injection. Lines established from such lung tumor nodules were more metastatic than the parent line following both iv and sc injection. These results show that the human melanoma cell line used in these studies contained cells with diverse metastatic potential and suggest that metastasis in the nude mouse results from the preferential selection of metastatic subpopulations.
Animals↗
Role of natural killer cells in host defense against cancer metastasis.
Explore the source record for details and available documents.
Animals↗
Enhancement of tumor metastasis and suppression of natural killer cell activity by beta-estradiol treatment.
Treatment of mice with 17 beta-estradiol leads to a selective inhibition of natural killer (NK) cell activity as measured by in vitro cytotoxicity against YAC-1 lymphoma and UV-2237 fibrosarcoma target cells. Activation of NK cells by polyinosinic-polycytidylic acid (poly I.C) and Corynebacterium parvum also was impaired in beta-estradiol-treated mice, whereas activation of tumoricidal macrophages was uncompromised. The beta-estradiol-induced suppression of NK cell activity was associated with a higher incidence of experimental and spontaneous pulmonary metastasis of the syngeneic UV-2237 fibrosarcoma and K-1735 and B16 melanoma tumors. Injection of poly I.C or C. parvum before i.v. tumor challenge markedly inhibited the development of lung tumor colonies in normal recipients, but it was less effective in beta-estradiol-treated mice. Adoptive transfer of normal spleen cells enhanced the NK cell activity and increased the resistance of beta-estradiol-treated mice against hematogenous tumor metastasis. Nude mice treated with beta-estradiol also exhibited a low level of NK cell activity and an enhanced susceptibility to metastasis of allogeneic tumor cells. The potential use of this in vivo model for studies of metastasis of human malignant neoplasms is discussed.
Animals↗
Environmental and genetic factors determine the level of NK activity of nude mice and affect their suitability as models for experimental metastasis.
In these studies we have evaluated the effects of age, genetic background, and housing conditions on the NK-cell activity of nude mice measured in vitro and resistance to tumor metastasis in vivo. BALB/cAnN nude mice exhibited lower levels of NK-cell-mediated cytotoxicity than age-matched N:NIH(S) nude mice maintained under similar housing conditions. The stronger response of N:NIH(S) nude mice was observed also after experimental activation of NK cells by Corynebacterium parvum. Nude mice maintained under barrier conditions have weaker NK-cell activity than mice maintained under conventional conditions. The incidence of experimental pulmonary metastases of allogeneic tumors injected into nude mice was inversely correlated with the levels of NK-cell-mediated cytotoxicity. Thus, 3-week-old BALB/cAnN nude mice raised under barrier conditions were more sensitive to development of experimental metastasis than age-matched N:NIH(S) nude mice maintained under barrier conditions or nude mice of either strain maintained under conventional conditions. In both strains, however, the relative differences in metastatic potential among the tumor cell lines observed in syngeneic recipients were maintained. We conclude that young BALB/cAnN nude mice raised under barrier conditions may provide a valuable in vivo model for studying metastasis of neoplasms.
Age Factors↗
Role of natural killer cells in control of cancer metastasis.
There is a close association between levels of natural killer (NK) cell activity and the ability of the host to eliminate circulating tumor cell emboli. Mice that exhibit low levels of NK-cell-mediated cytotoxicity (3-week-old syngeneic mice, 3-week-old allogeneic nude mice, cyclophosphamide- or beta-estradiol-treated mice, and beige mice) also exhibit enhanced survival of tumor cells in the vascular bed of the lung and increased incidence of pulmonary tumor metastasis. Conversely, hosts with high NK cell activity (adult nude mice and syngeneic mice treated with NK-cell-stimulating biological response modifiers (BRM) ) are very resistant to metastasis. Lymphoid adoptive transfer studies have shown that the effector cell responsible for the antimetastatic activity is the NK cell. In these studies, NK cells were highly effective in destroying circulating tumor cells before their extravasation into the organ parenchyma, whereas they exerted only a minimal inhibiting effect on already established micrometastases. The ability to activate NK cells selectively (without subsequently inducing suppressor macrophages) provides a valuable tool for the evaluation of the role of activated NK cells in therapy of tumor metastasis. The validity of this approach is supported by the finding that NK cells activated by BRM are effective in killing, both in vivo and in vitro, solid tumor cells that developed NK-cell-resistance as a result of adaptive growth in vivo or selection during the metastatic process. An understanding of the mechanisms that regulate NK cell activation or suppression as well as elucidation of the circulatory patterns and anatomical compartmentalization of activated NK cells will help achieve a sustained systemic and/or in situ activation of NK cells which may prove effective in the control of cancer metastasis.
Aging↗
Hypothermic ischemic arrest versus hypothermic potassium cardioplegia in human beings.
To determine if the addition of potassium enhances the myocardial protective effect of intracoronary perfusion hypothermia during aortic cross-clamping, 50 patients undergoing aortocoronary bypass grafting were studied in a randomized, prospective, double-blind fashion. Twenty-six patients received a cold crystalloid solution infused with a handheld syringe into the root of the cross-clamped aorta every 20 minutes, and 24 patients received the same solution but with 25 mEq/L of potassium chloride added, infused in a similar manner. Both groups were analyzed by mortality, rate of perioperative myocardial infarction (electrocardiographic changes, MB-CPK enzyme release, and preoperative and postoperative gated cardiac blood pool scans), intraoperative hemodynamic changes, intraoperative lactate determinations, postoperative arrhythmias, and requirement for pressor or intraaortic balloon pump support. One patient in the potassium cardioplegia group died (massive pulmonary embolism), and none in the hypothermic perfusion group died. Possible perioperative myocardial infarction was diagnosed by more than one marker in 4 of 26 patients in the hypothermic perfusion group and 5 of 24 patients in the potassium group (p = 0.61). There were no differences between the two groups in terms of hemodynamic changes, lactate production, postoperative arrhythmias, or the need for postoperative hemodynamic support. This study in human beings could not demonstrate a specific protective effect of potassium, beyond that afforded by myocardial perfusion hypothermia and wash-out. The data suggest that myocardial hypothermia, achieved through cold intracoronary arterial perfusion, may be the most important beneficial component of so-called cardioplegia for attaining effective intraoperative myocardial preservation in human beings.
Arrhythmias, Cardiac↗
Murine lymph node natural killer cells: regulatory mechanisms of activation or suppression.
The kinetics and organ distribution patterns of lymph node natural killer (NK) cell activation or suppression were found to vary according to the type, dose, and route of administration of Corynebacterium parvum or polyinosinic-polycytidylic acid (poly I . poly C). Activation of lymph node NK cells by local injections of C. parvum into the footpad or the peritoneum was restricted to the regional lymph nodes; contralateral and distant lymph nodes were not involved. This selectivity persisted even though splenic and peripheral blood NK cells were strongly activated by the same treatment. Conversely, poly I . poly C induced systemic activation of NK cells without selectively activating the regional lymph nodes. The decline of NK cell activity observed 2 weeks after C. parvum treatment was associated with a state of unresponsiveness to a second injection of NK cell stimulants. The expression of C. parvum-induced suppression could be systemic or restricted to the regional lymph nodes. Possible mechanisms for the anatomical compartmentaliztion of NK cell activation or suppression and the implications for the control of tumor growth and dissemination in vivo are discussed.
Animals↗
Inhibition of experimental tumor metastasis by selective activation of natural killer cells.
The antitumor activity generated by selective activation of natural killer (NK) cells was studied in vitro and in vivo. Unlike Corynebacterium parvum CN6134, which activated both NK cells and macrophages, periodate-oxidized C. parvum CN6134 lost the ability to activate macrophages but retained almost all the NK-stimulating capacity of the untreated bacterium. The "inactive" C. parvum strain CN5888 also induced a modest, but selective, activation of NK cells. The enhanced NK cell-mediated cytotoxicity was expressed against YAC-1 lymphoma, UV-2237 fibrosarcoma, and B16 melanoma target cells in vitro and was manifested in vivo by increased destruction of circulating tumor cells and the inhibition of hematogenous tumor metastasis. Periodate-treated C. parvum was as effective in inhibiting the formation of B16 melanoma pulmonary metastases as was untreated C. parvum. In both cases, the inhibiting effect corresponded closely with the kinetics of NK cell activation.
Animals↗
In vivo models for studies of human tumor metastasis.
Explore the source record for details and available documents.
Animals↗
In vivo isolation of a metastatic tumor cell variant involving selective and nonadaptive processes.
An investigation was done to determine whether spontaneous metastases that develop in a C3H mouse bearing the syngeneic UV-2237 fibrosarcoma are derived from specialized subpopulations of cells or represent an adaptation process to a local (organ) environment. Inbred C3H mice received sc injections of parent tumor and, 9 weeks later, 5 individual pulmonary metastases were harvested and established in culture. Cells from each of these metastases colonized in the lungs of normal recipient mice with significantly greater efficiency than did cells from the parent tumor. Mice received injections iv of cells from a cloned line of UV-2237 that produced few lung metastases. Cells from these metastases did not colonize in the lungs at a dramatically higher rate than did the parent clone. The growth per se of tumor cells into colonies in the lung is not sufficient by itself to endow cells with metastatic properties. The selection in vivo of cells with enhanced lung colonization does not require that the lung be used as a selective organ. A cell variant was selected for enhanced capacity to grow in the peritoneal cavity of normal recipients. This cell line was also found to have a high capacity to colonize in the lungs following introduction into the circulation. It was concluded that the growth of metastases in this murine tumor system was not due to adaptive processes but rather to selection by intrinsic properties of tumor cells.
Adaptation, Physiological↗
Definitive evidence that natural killer (NK) cells inhibit experimental tumor metastases in vivo.
Effector lymphoid cells that inhibit hematogenous tumor metastasis in normal unimmunized mice were studied. Mice pretreated with cyclophosphamide (Cy) exhibited a diminished ability to destroy circulating tumor cells, which, in turn, caused an increased incidence of experimental pulmonary metastasis. Adoptive transfer of spleen cells from unimmunized syngeneic donors abrogated the Cy-induced enhancement of metastasis formation. The effector cell active in these adoptive transfer experiments was sensitive to treatment with specific anti-NK-1.2 antibodies and complement. This treatment was shown by in vitro tests to deplete or inactivate NK cells selectively. These findings provide direct evidence that NK cells play a significant role in the inhibition of hematogenous tumor metastases in vivo.
Animals↗
Expression of metastatic potential of allogenic and xenogeneic neoplasms in young nude mice.
Several different mouse and rat tumors were injected s.c. or i.v. into specific-pathogen-free young (3-week-old) and adult (6-week-old) nude mice. All tumors grew s.c.; however, following i.v. injections, only metastatic neoplasms produced visible pulmonary tumor foci in the 3-week-old (but not in the 6-week-old) nude mice. The quantitative differences in metastatic potential among tumor lines and clones observed in syngeneic hosts were maintained also when 3-week-old nude mice were used. The enhanced survival of tumor cells in the lungs and the large numbers of visible pulmonary metastases observed in the young nude recipients correlated closely with the low levels of natural killer cell activity detected in 3-week-old (but not in 6-week-old) nude mice. In vivo activation of natural killer cells by treatment of mice with polyinosinic-polycytidylic acid or Corynebacterium parvum, 24 hr prior to tumor challenge rendered th 3-week-old nude mice resistant to development of metastases. We conclude that specific-pathogen-free 3-week-old nude mice, which lack functional T-lymphocytes and demonstrate low natural killer cell activity, could serve as an in vivo model to ascertain the metastatic potential of allogeneic and xenogeneic tumors.
Animals↗